Endometrial Cancer - MR staging

Endometrial cancer represents the fifth most common cancer type in women and - together with cervical cancer - accounts for 0,7% of all cancer related deaths [ref].

The primary treatment for endometrial cancer is surgical resection.
The key risk factors in endometrial cancer to assess on imaging are the depth of myometrial invasion, invasion into the cervix, bladder or rectum and lymph node involvement.

Clinical factors include obesity, tamoxifen use, hyperinsulinemia, prolonged exposure to unopposed estrogen often caused by nulliparity,  and infertility associated with polycystic ovarian syndrome.
Although most cases of endometrial cancer are sporadic, 5-10% are hereditary, usually related to the Lynch syndrome.

Endometrial cancers are mostly endometroid adenocarcinomas (80-90%), which have a relatively good prognosis. The remaining 10-20% of endometrial cancers are mainly serous carcinoma, clear cell or carcinosarcoma which all have a poorer prognosis.     

Uterine anatomy is best displayed on T2-weighted MRI.
During the reproductive period, three distinct zonal layers can be recognized: the endometrium (high signal), the junctional zone (low signal), and the myometrium (relatively high signal).
The outer surface of the uterine myometrium, the serosa, can be recognized as a thin hypointense line.

The zonal MRI anatomy of the uterus and cervix varies with age.
During the reproductive age the different layers of the uterus and cervix are well recognizable and the muscular part of the uterine wall can be highly vascularized.
In this 30-year-old woman an IUD (recognized as a hypointense linear structure) is present in the uterine cavity.

In postmenopausal women the zonal anatomy becomes less visible and the cervical stroma, junctional zone and myometrium appear more homogeneously hypointense on T2W-images.
With age, the female reproductive organs gradually become smaller with a more pronounced loss in volume for the uterus compared to the cervix.

The position of the uterus can vary depending on the angle between the cervix and uterus, i.e. anteflexion or retroflexion and the angle between the vagina and cervix, i.e. anteversion or retroversion.

MR reporting checklist

The MRI report in endometrial cancer should address the key risk factors listed in the table in order to determine the most appropriate treatment strategy.

Additional factors that are relevant for surgical planning and that should be included in the report are:

• Total uterine size
• Benign conditions such as endometriosis or leiomyoma
• Anatomical variants

Tumor size

Depending on the age of the patient, endometrial tumors can present mildly hyperintense (see image) or hypointense (in younger patients) compared to the normal myometrium.
They are typically well-recognizable on T2 weighted images.
The morphology of the tumor can vary from a well-delineated mass to a more diffuse tumoral thickening growing along the endometrial lining.

Image
Example of a mass-forming endometrial tumor, which are typically easiest to measure. It is important to measure the longest tumor diameter.
In this case, the longest tumor diameter is best visualized on the sagittal plane. 

In cases with more diffuse tumoral thickening along the endometrial lining, it can be more difficult to measure the tumor size.
Check the tumor in multiple planes and look for the longest possible tumor size.
In this case, the longest tumor diameter is best visualized in the axial plane (figure).

Note that the normal endometrial thickness varies between pre- and postmenopausal women, with various cut offs reported in literature:

• Premenopausal: ≤16 mm (varying thickness during different phases of menstrual cycles)
• Postmenopausal (usually 1-5 mm):

            - No vaginal blood loss:  < 11 mm
            - Vaginal blood loss and/or on tamoxifen: < 5 mm

These thresholds have been proposed to warrant further gynaecological evaluation.
Final decisions about further investigations should always be made on a case-by-case basis, taking into account clinical symptoms, tamoxifen use and risk factors for developing endometrial pathology.

Sometimes tumors are less well visible and difficult to delineate on T2-weighted images.
In such cases the DWI (and ADC map) and T1 post contrast series can help to better delineate and measure the tumor.

Most endometrial cancers show distinctly high signal on high b-value DWI and are hypovascular compared to the surrounding myometrium on contrast-enhanced T1-weighted images.  

Atypical enhancement patterns

Note that not all endometrial tumors are hypovascular compared to the myometrium.

The case on the left shows an example of an endometrial tumor with sarcomatoid components which can show strongly enhancing components. 

Another example of a tumor that does not show a typical hypovascular appearance, but instead shows diffuse enhancement that is almost similar to the enhancement of the surrounding myometrium.
This is a case of high grade endometrial stroma sarcoma. 

Total uterine size

The total uterine size is important to report as this will impact the surgical strategy of a transvaginal versus laparoscopic or open transabdominal approach. 
If the total uterine size is too large (e.g. >10 cm), this will be a contra-indication to perform transvaginal or laparoscopic surgery.  

The uterine size is typically measured in the sagittal plane in 2 dimensions: craniocaudal (including the cervix) x anteroposterior (figure).

Myometrial invasion

Measuring the depth of myometrial invasion is typically done using a combination of the sagittal and the perpendicular axial plane.

It entails a 3-step approach (figure):

1. draw a line parallel to the inner myometrium
2. measure the maximum tumor extent into the myometrium
3. determine the full myometrial thickness (dashed line)

The ratio between 2 and 3 represents the percentage of myometrial invasion.

An invasion depth of < 50% of the full myometrial thickness is considered ‘superficial’ invasion.
An invasion depth of > 50% is considered deep invasion which is associated with a higher risk for lymph-vascular space invasion, which in turn is associated with higher tumor grade, risk for nodal metastases and increase risk for tumor recurrence.

Note that according to the new FIGO classification it is important to explicitly mention the presence or absence of any myometrial invasion, whether superficial or deep.
The absence of myometrial invasion is particularly relevant to select patients eligible to undergo fertility sparing treatment (see section on fertility preservation below).

Images
Myometrial invasion is shown as a disruption of the normal low signal of the junctional zone on T2W-image and as interrupted enhancement of the endometrial-myometrial interface on post-contrast images, where endometrial cancers appear hypointense compared to the enhancing myometrium.
The myometrium has a full thickness of 21 mm, but the invasion into the myometrium is only 6mm (6/21=28%, indicating < 50% invasion).

Pitfall - Expansion versus invasion

It is important to differentiate expansion from invasion.
Sometimes there can be enormous expansion without any invasion.

Images
There is obvious expansion of the uterine cavity, but without any signs of myometrial invasion.
Note how we can nicely recognize a completely intact hypointense junctional zone to confidently rule of invasion of the myometrium.     

Benefit of DWI

Sometimes the tumor is difficult to delineate on T2W-images because it is almost isointense compared to the myometrium.
In such cases, DWI helps in differentiation between tumor and myometrium.

Images  
On the T2w-image the tumor is almost isointense to the myometrium.
The DWI-image shows that there is myometrial invasion but less than 50%. 

Cervical Stromal invasion

Cervical stromal invasion can be detected as an extension of tumor signal with corresponding disruption of the normal low signal of the cervical stroma on T2W-images.
It can also be appreciated as a disruption of the normal cervical stromal enhancement on CE images, or as extension of high tumor signal on high b-value DWI.

Image
There is an endometrial tumor that invades the cervical stroma anteriorly.
There is extension of the intermediate tumor signal that disrupts the normal hypointense signal of the cervix (arrow).

Pitfall – endocervical tumor protrusion

Cervical stromal invasion should be distinguished from tumor protrusion into the cervical canal.
Tumor protrusion can cause widening of the cervical canal with consequent thinning of the cervical stroma due to mass effect.

Image
Note that there is no actual extension of tumor signal into the cervical stroma.
Therefore there is no cervical stromal invasion.  

Extrauterine extension (incl. bladder and rectal extension)

The vast majority of endometrial cancers are confined to the uterus at the time of diagnosis, as clinical symptoms (blood loss) typically occur at an early stage.  
Extrauterine extension and invasion of the bladder or rectal wall are therefore rarely observed on MRI.
When we do see it, it entails advanced stage disease which should be clearly stated in the report as it will affect the surgical approach.

Image
This is a rare example of a locally advanced endometrial cancer that grows beyond the uterine serosa on the dorsal side where it invades the sigmoid colon (arrow)

Another example of an endometrial tumor (with serous components at histology) that shows extensive cervical stroma invasion and a separate tumor deposit (metastasis) in the vaginal wall.  

Lymph node staging

When staging endometrial cancer, the regional (N-stage) lymph nodes include all lymph nodes in the pelvis except the inguinal lymph nodes, which are considered distant (M-stage) nodes.

Para-aortic nodes up to the level of the renal veins are also considered regional nodes.
Nodes above the level of the renal veins are considered distant metastases.

In addition to MRI, lymph node staging in endometrial cancer is generally performed with the use of sentinel lymph node mapping and/or lymphadenectomy during surgery. PET-CT is not routinely performed despite the fact that it has an excellent diagnostic performance for detecting lymph node metastases preoperatively (reference).

Hematogenous metastases

Endometrial cancer most often metastasizes to the peritoneum or lung. It is not uncommon that the local disease is relatively limited, but there is still hematogenous tumor spread.

 

Images
Although the endometrial tumor is difficult to recognize on CT (remember that for local staging we need MRI) it appears to remain confined to the uterus with no signs of a mass extending beyond the uterus.
There are, however, obvious signs of peritoneal metastases as there is diffuse ascites (black arrow) and clearly visible omental cake (white arrows).  

The scanning parameters are shown in the table.

The MR protocol also includes:

• Use a field strength of 1.5T or higher, using a pelvic phased-array coil.
• Patient in supine position
• Scheduling according to the menstrual cycle is not required.
• Fasting (4-6 hours)
• Empty bladder
• Use of anti-peristaltic agents (Buscopan or Glucagon)
• Saturation bands on the subcutaneous fat both anterior and posterior is recommended.
• Contrast-enhanced images acquired after 2.5 minutes provide the best contrast between the tumor and the myometrium. 
  
  

According to the ESUR guidelines the contrast-enhanced images can either be acquired as part of a DCE acquisition or using a single-phase axial acquisition, though with the update of the FIGO guidelines future recommendation may advocate for the routine use of DCE.

DCE-MRI offers the advantage of multiphase imaging:

• Early phase images (30-60 seconds after injection) are optimal to evaluate sub-endometrial enhancement, which is important to assess patients’ eligibility for fertility sparing treatment (see section on fertility preservation below).
• Equilibrium phase images (120-180 seconds) are the best to evaluate the depth of myometrial invasion 
• Delayed phase images (4-5 minutes) are optimal for the detection of cervical stromal invasion

Sequence planning

The MR sequences are planned relative to the long axis of the uterine cavity.
The axial plane is perpendicular to the long axis of the uterine cavity.
The coronal plane is parallel to the long axis.

Pitfall: variations in uterine anatomy

The position of the uterus needs to be taken into account and the perpendicular and parallel MRI sequences need to be planned accordingly.

In this case there is anteversion of the cervix and retroflexion of the uterus.
The coronal series are planned parallel to the uterine cavity (yellow box), while the axial series are planned perpendicular to it (blue box).

Here another example showing the cervix in retroversion and uterus in anteflexion.
See how this variation in position impacts corresponding sequence planning.

Pitfall: variations in uterine position

Note that the position of the uterus can vary significantly between and even during MRI examinations based on for example the degree of bladder filling.

These variations, as well as variations in version and flexion described above can pose a real challenge for MRI technicians.
MRI technicians should therefore receive proper training on how to recognize and handle these variations.
Moreover, when technicians are in doubt, radiologists should be available during scanning to supervise the examination and offer advice on for example bladder voiding.

For endometrial cancer, fertility preserving treatment consists of hormonal therapy which is not considered standard of care treatment.
It is only offered in selected patients and secondary surgery is typically performed once the family is complete. 
The Table shows the main selection criteria for fertility preservation in  endometrial cancer.

Confinement of the tumor to the endometrium is confirmed by the presence of an intact sub-endometrial line on early-phase DCE images (35-40 sec).
As such, DCE imaging is mandatory to stage endometrial cancer in young patients in whom fertility preserving treatment is considered as a potential treatment option.

Image
Example of an endometrial tumor that is confined to the endometrium.
There is a smooth interface between the tumor and junctional zone on T2W MRI.
Though not routinely done, it can be helpful to fuse the T2W and high b-value diffusion-weighted images.
In this case the fusion images with the DWI in color overlay confirm the absence of myometrial invasion.
The most accurate technique to confirm this is DCE.
Early phase images at 30-60 seconds after injection are optimal to evaluate sub-endometrial enhancement, which is important to assess patients’ eligibility for fertility sparing treatment.

In this case the subendometrial line is intact on the early phase DCE images (arrows), indicating no myometrial invasion.    

The International Federation of Gynaecology and Obstretrics (FIGO) staging system that is most commonly used to stage cervical and endometrial cancers was traditionally designed as a clinical surgical staging system.
However, current evidence and clinical guidelines recommend to include imaging findings, in particular MRI for staging and treatment planning as it provides crucial information on tumor size and depth, extent of invasion into surrounding organs and structures, and lymph node status, which are essential in choosing the most appropriate treatment strategy.
An overview of the current 2023 FIGO stages for cervical and endometrial cancer is provided in the overview Table on the left but we refer readers to the complete FIGO guidelines for more detailed info [ref].

Clinical classification systems (such as FIGO) are constantly evolving to accommodate new clinical insights, novel prognostic markers and treatment developments. For example, the risk classification and clinical guidelines for endometrial cancer have recently been updated to take into account different molecular subtypes that can influence adjuvant treatment recommendations, especially in high-grade/high-stage tumors. 
The new FIGO 2023 endometrial classification recommends including molecular profiles, which are divided into four groups (POLEmut; MMRd; p53abn; and NSMP) each with different prognostic profiles that in the current version of the FIGO staging system modify the final stage [ref].

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